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Hello all!
I am trying to come up with a good method of solubilizing a very
hydrophobic compound for IV dosing. I have tried a wide range of
solvents and have tried pH adjustments. The best I have come up with
so far is a solution of 18% DMSO (v/v), 6% propylene glycol (v/v) and
10% sodium citrate (w/v). This solution appears to solubilize the
compound fairly well up to a maximum concentration of 5mg/mL.
My concern is that I have read that the organic cosolvents should be
limited to 20% of the solution. So my first question is whether others
have heard and adhere to this rule? My second question is whether it
would be better to adhere to this rule and use a larger volume for
dosing (perhaps as much as 2mL/kg) in order to get a sufficient dose
in, or whether it would be better to use a higher percent organic
cosolvents and a smaller dosage volume?
I am a grad student so I dont have SOPs to follow. If anyone could
offer example SOPs for this situation or references, it would be much
appreciated.
Alene McCoy
PhD Candidate
School of Pharmacy
Washington State University
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Hello Alene,
You didn't mention your species of test subject.
If you are using rodents, an upper limit of 1g DMSO per healthy rat
should
be ok. Using a large injection volume will slow down your push rate,
and
depending on the conduction and metabolic rates of your compound, you
may
need to take the push rate into account to extract accurate
parameterization
of the drug.
Hope it helps.
-Shawn
Shawn D. Spencer, Ph.D., R.Ph.
Assistant Professor of Biopharmaceutics
Florida A&M College of Pharmacy
Dyson Bldg., Rm 227
Tallahassee, FL 32307
shawn.spencer.-at-.famu.edu
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I would stay clear of organic solvents if at all possible. Other
methods for increasing solubility could include a cyclodextrin
derivative, eg, hydroxypropyl-beta-cyclodextrin, or sulfobutylether
cyclodextrin (Captisol), adsorb onto albumin, possibly a surfactant to
form micelles, eg, Tween 80.
Any of the above are worth trying, particularly for animal
experiments. If you eventually wish to go into human subjects, I would
use hydroxypropyl-beta-cyclodextrin first, only because the company
that markets Captisol makes life a little difficult for purchasing and
signing life away about use of its product. Apart from that, the
sulfobutylether derivative has enormous promise, depending on the
molecular properties of the test compound.
Des Williams
--
Des Williams, PhD, FRACI
Sansom Institute for Health Research
School of Pharmacy and Medical Sciences
University of South Australia
North Terrace
Adelaide
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Hi Alene,
in general DMSO isn`t a good choice for PK with small molecules, as
DMSO is a highly potent CYP3A4 inhibitor.
In such high amout you will get a good chance to observe some "DDI"
with your NCE, at least try to check your compound in vitro ( i.e.
microsomal) w/o DMSO.
Most small rodent (mice, rat and gerbil) can get up to 5 ml/kg i.v.
A good ref. is Strickley, Pharm Res, 21(2), 201-230 (2004) for
formulation dev.
Finally maybe it is a good idea to reduce the dose to prevent you from
fishy results due to poor physchem properties.
kind regards
Dirk
--
Dr. Dirk Scharn
Senior Scientist, DMPK
Jerini AG
Invalidenstrasse 130
10115 Berlin, Germany
eMail: scharn.-at-.jerini.com
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Dear Alen,
Is that for acute (or) Chronic dosing?. For single shot
18% of DMSO will be safe, were as for repeated dosing there will be
toxicity issue. For IV dosing the formulation should be neutral pH and
there should not be any precipitate .aaa.10 times dilution with PBS. So
many literature are available on solubilisation of insoluble drugs,
specific example would be An intravenous formulation decision tree for
discovery compound formulation development by Yung-chi
leeInternational Journal of Pharmaceutics, Volume 253, Issues 1-2, 6
March 2003, Pages 111-119.
Regards
Devarajan,
Formulation Research.
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What compound is your compound similar to? Try using a software program
like Simulations Plus ADMET(www.simulations-plus.com), ACD's ILAB
(www.acdlabs.com)or Terrabase (www.terrabase-inc.com).
There are others out there as well. They will usually save lots of
time as
well as mg of your compound.
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Hi Ed,
Do you mean use a software program to find out what compound my
compound is similar to? Or can the software be used to somehow
simulate solubility in various solutions?
Alene McCoy
PhD Candidate
School of Pharmacy
Washington State University
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Most software will allow you to "draw the molecule" Then they use
various
algorithms to estimate pKa, aqueous and organic solubility, even pH
effects
from the drawn structure.
You can also do the foot/fingerwork and identify similar compounds and
their
solubilities using the Merck Index.
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Dear McCoy:
I haven't heared this rule, but in some case, cosolvents would have an
effect on our compound's stability and activity.
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The best way to deal with insoluble compounds for IV administration is
to administer them at microdose levels ie no more than 100
micrograms. PK under these conditions has been shown to be linear
with pharmacological doses.
Professor R Colin Garner BPharm PhD DSc FRCPath
Garner Consulting Services
colin.garner.at.xceleron.com
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Colin and Colleagues,
I think these concepts are interesting points of discussion.
For one, I am curious how microdose levels can provide useful
information
for extrapolation into what may be a nonlinear PK therapeutic range.
Secondly, as Ed mentioned, obtaining estimates for native or intrinsic
solubility characteristics in silico may be interesting, but its not
obvious
to me how that provides a platform for practically optimizing cosolvent
concentrations or choice of cosolvent.
Lastly, CYP inhibition is an interesting caveat. Unlike HT microsomal
probe
assays which may use 20% DMSO against a background control for the less
sensitive isoforms, the in vivo case is diluted 300 to 1 or more. I
assume
preclinical reports of DMSO DDI are not widely reported as an IV
formulation
won't make it to Phase I, but perhaps someone knows a study on in vivo
CYP
inhibition/DDIpk by DMSO?
Many thanks,
-Shawn
Shawn D. Spencer, Ph.D., R.Ph.
Assistant Professor of Biopharmaceutics
Florida A&M College of Pharmacy
Dyson Bldg., Rm 227
Tallahassee, FL 32307
shawn.spencer.-a-.famu.edu
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An eye or a head's up must be cautioned when selecting solvents in
preclinical which may have there own associated toxicity, or which
will not
be permitted in clinical trials. Better to find another vehicle or
carrier
and build up hope based on "good stone".
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Hi,
My own approach to this problem would be to use current guidelines
around the acceptable levels of solvents/co solvents in IV
formulations to prepare a structured experimental design matrix (based
on mixture design methods). Using a number of excipients, varied
across suitable concentrations, as the factors investigated and the
solubility of the molecule in each vehicle as the measured response, a
surface response predictive model could be generated. The ideal
situation being that the statistical analysis of the data would allow
the generation of a vehicle which combines maximum solubility within
the set limits of organic solvent levels.
As I think has been mentioned, you have not stated what species you
intend to dose to. The following is the limits I stick to when
designing formulations for preclinical use in the rat.
Max single IV dose volume ml/Kg
PEG 400 0.5 (50%)*
Propylene glycol 0.6 (15%)
Glycerol 0.4 (15%)
Ethanol 0.25 (15%)
Polysorbate Tween 80 0.25 (5%)
Dimethyl acetamide 0.4 (40%)
Dimethyl sulphoxide 0.5 (40%)
Lipids Max single IV dose volume ml/Kg
Corn oil 10
Olive oil 10
Soybean oil 10
Miglyol 10
Some additional guidelines on the vehicle:
pH should be between 5 and 9
Highly viscous solutions should be avoided
Conor
Formulation Development Scientist
Ireland
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The guideline to choose vehicle for IV administration of insoluble
compound vary from lab to lab and to say the least, there is no
universal guideline to choose solvents for solubilization of insoluble
compounds. Having been in NCE development for handful years, I can
share that it is a rationale approach by pharmaceutical scientists
that is instrumental in addressing solubilization issues, be it
related to IV or oral adminsitration.
The literature is in abundance in this regard, but I would prefer
using customized approach as per the scaffolds. Its not about
selection of solvent (or co-solvent), but it is about rationale. If
the insoluble compound offers a potential to ionize or form ion pair,
it can be utilized in synergy with other solubilizing mechanisms. If
the compound does not offer any ionizable centre, then micellar
solubilization with or wothout a co-solvent approach can be explored.
However having said that, a log linear relationship is expected to
exist invariably with co-solvent (i.e., higher solubilization at
higher volume fraction and huge crash out upon dilution being log
linear solubility curve) and hence such approaches generally do not
suffice if the compounds needs to be solubilized more than 1 mg/mL.
Even then if co-solvent based approach needs to be followed, an
efficient throughout approach can be used to screen co-solvent or
solvent compositions (like using a 96-titre plate model), and this
seems to work most of the times.
Hope this will help.
--
Dr. Vaibhav Sihorkar
Head (Pharmaceutical Development)
Aurigene Discovery Technologies Ltd.
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Dear Conor,
Many thanks for sharing the wonderful information.
But the factorial design for the formulation matrix considering the
individual solubility of the active in each of the vechicle component
may prove sometimes more rigorous.
In experimental based on mixture design methods, one cannot stick to
the single regime a of the formula, though they may be similar for the
array of the compounds within the range of the solubility limits. At
the same time, supersaturation will be the big puzzle and the
practical hurddle that would not make the statistical design that much
predictive.
Amrit
--
Dear Vaibhav
Yes,
The answer is more methodical. If the scaffolds down the line are of
the similar profile, for the cosolvent appraoch, one can do the phase-
solubilty behavior studies prior to using the approach. Based upon the
inoizable motiffs, in-situ salt formation and pH adjustment approach
will work nicely. If one needs to scale the solubility really higher
then, high enery solids (amorphous and solid dispersion) with the
benchtop istruments are the better one.
Amrit
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I agree with you all guys in all aspects however a rational approach
is good
in discovery research especially when you are doing IV for determining
the
absolute bioavailability of the compound. A lot of useful discussions on
solubility can be found from the archives in this forum for the past
seven
years.
I would like to add one more solvent which I normally use instead of
DMSO is
NMP (N-2-methyl pyrrolidine) which can be used up to 15-20% in your IV
formulation. And of course you have to play with other cosolvents what
Conor
has mentioned in his earlier mail.
Regards,
Kanthikiran
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